Cerebrospinal fluid purification system

ABSTRACT

The present invention provides methods and systems for conditioning cerebrospinal fluid (CSF) by removing target compounds from CSF. The systems provide for a catheter flow path and exchange of a majority volume portion of CSF in the CSF space. The removal and/or delivery of specific compounds can be tailored to the pathology of the specific disease. The removal is targeted and specific, for example, through the use of specific size-exclusion thresholds, antibodies against specific toxins, and other chromatographic techniques, as well as delivery and/or removal of targeted therapeutic agents.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/548,554, filed Aug. 22, 2019; which is a continuation ofU.S. patent application Ser. No. 15/410,219, filed Jan. 19, 2017, nowU.S. Pat. No. 10,398,884; which is a continuation of U.S. patentapplication Ser. No. 13/801,215, filed Mar. 13, 2013, now U.S. Pat. No.9,895,518; which is a continuation of U.S. patent application Ser. No.12/444,581, filed Jul. 1, 2010, now U.S. Pat. No. 8,435,204; which isthe U.S. National Phase entry of International Patent Application No.PCT/US2007/080834, filed Oct. 9, 2007, which claims the benefit of U.S.Provisional Application No. 60/828,745, filed Oct. 9, 2006. Theentireties of the above-captioned applications are incorporated byreference herein for all purposes.

FIELD OF THE INVENTION

The invention pertains generally to medical devices and methods. Moreparticularly, the present invention relates to devices, systems methodsand kits for removal of toxins from the cerebrospinal fluid (CSF). Morespecifically, the method and system can be used to diagnose and treatdisorders affecting the central nervous system (CNS) by measuring andmodifying the chemical composition of CSF.

BACKGROUND OF THE INVENTION

Others have described devices for the handling and/or removal ofcerebrospinal fluid (CSF) to and from a patient.

For example, several patents disclose various methods for diverting orshunting CSF from the CSF space (ventricle, spinal column) to anotherportion of the body (e.g., abdomen, peritoneal cavity). See, e.g., U.S.Pat. Nos. 2,969,066; 3,889,687; 6,575,928 and 7,118,549. Others havedescribed administering therapeutic agents to the CSF space, but do notdisclose removing the CSF. See, e.g., U.S. Pat. Nos. 5,531,673;6,056,725; 6,594,880; 6,682,508 and 6,689,756. Generally, thetherapeutic agents are locally delivered to the brain but not to thegreater cerebrospinal fluid space, which includes the brain and thespine. Others disclose removing CSF, but generally do not administertherapeutic agent or any other fluid. See, e.g.; U.S. Pat. Nos.3,889,687; 5,683,357; 5,405,316 and 7,252,659.

Devices exist having both input and output catheters for administeringtherapeutic agents or synthetic CSF and removing endogenous CSF, but theclose spatial placement of the inflow and outflow catheters do not allowfor flow of CSF throughout the cerebrospinal fluid space or full CSFexchange that provides access to the complete intracranial andintraspinal CSF volume. See, e.g., U.S. Pat. Nos. 4,378,797; 4,904,237;6,537,241 and 6,709,426.

Furthermore, publications disclosing the exchange of CSF describereplacing endogenous CSF with synthetic CSF replacement fluid. See,e.g., U.S. Patent Publication No. 2003/0065309; and PCT Publication Nos.WO 01/154766 and WO 03/015710. In this way, the concentration of thetoxic species may be diluted but not removed. It has been proposed totreat drug overdose or removal of tumor cells to clear debris beforeimplantation of a ventriculo-peritoneal shunt shunt system. Such anapparatus is unnatural in that it requires flushing the entire systemwith an artificially produced solution rather than removing the toxinsof interest from the patient's endogenous CSF, requires liters ofinstilled replacement fluid to be delivered on a regular basis, isneither targeted nor focused for removal of specific toxins of interestand is only practical in an acute setting where liters of fluid could beinstilled. See, e.g. PCT Publication No. WO 01/54766.

Various devices aimed at accessing the CSF or indirectly targeting thenervous system exist, however there exists no CSF purification systemthat allows for the direct, targeted, logical and disease-specificremoval of one or more of target compounds or the use of a dual ormulti-lumen catheter that influences or controls CSF flow, mixing andefficiency of turnover.

It is desirable to provide a method and system for processing andremoval of one or more target compounds from the CSF of a patient.Recently, a treatment for Alzheimer's disease was suggested which reliedon removal of CSF by diversion of the fluid from the brain (ventricularsystem) to another portion of the patients body (e.g. abdomen/peritonealcavity) using a modified ventriculo-peritoneal shunt system. See, e.g.,U.S. Pat. Nos. 5,980,480 and 7,025,742. By continuously draining CSF ata low rate, the rationale was that the body's daily production of newCSF would dilute the concentration of contaminating substances remainingin the endogenous CSF. Such a system has several inherent limitations.The rate at which the concentration of toxic species is lowered ismediated by passive flow, is very slow, addresses only a fraction(milliliters) of the total CSF volume per hour, is not targeted orfocused in removing specific items of interest and does not preventreabsorption of toxic species back into the systemic circulation andthereby back into the CSF. See, e.g. U.S. Pat. Nos. 5,980,480;6,264,625; 6,689,085.

The present invention addresses this and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention provides systems and methods for conditioningcerebrospinal fluid (CSF).

Accordingly, in a first aspect, the invention provides methods forconditioning cerebrospinal fluid (CSF) in a patient. In someembodiments, the methods comprise:

-   -   a) removing CSF from a first location in a CSF space of the        patient;    -   b) conditioning the removed CSF; and    -   c) returning the conditioned CSF to the patient at a second        location in the CSF space; wherein the removing and returning        steps are performed concurrently during at least a portion of a        conditioning treatment.

In another aspect, the invention provides methods for conditioningcerebrospinal fluid (CSF) in a patient, the methods comprising:

-   -   a) introducing a catheter apparatus through a spinal (e.g.,        sacral, lumbar, thoracic, cervical) access site into the spinal        CSF space of a patient;    -   b) advancing the catheter apparatus through the spinal CSF space        cranially (toward the brain) such that a distal port and a        proximal port on the catheter apparatus are disposed within the        CSF space and spaced-apart by a preselected distance;    -   c) withdrawing CSF through one of said ports;    -   d) conditioning the withdrawn CSF; and    -   e) returning the conditioned CSF through the other of said        ports.

In another aspect, the invention provides methods for conditioningcerebrospinal fluid (CSF) in a patient, the methods comprising:

-   -   a) introducing a catheter apparatus into a brain ventricle or        into the subarachnoid space of a patient;    -   b) advancing the catheter apparatus into the spinal CSF space        such that a distal port and a proximal port on the catheter        apparatus are disposed within the CSF space and spaced-apart by        a preselected distance;    -   c) withdrawing CSF through one of said ports;    -   d) conditioning the withdrawn CSF; and    -   e) returning the conditioned CSF through the other of said        ports.

In another aspect, the invention provides methods for conditioningcerebrospinal fluid in a patient, the methods comprising:

-   -   a) introducing a catheter apparatus into a brain ventricle of a        patient;    -   b) adjusting spacing between a pair of ports on the catheter        apparatus so one port lies on one side of the ventricle and the        other port lies on another side of the ventricle;    -   c) withdrawing CSF through one of said ports;    -   d) conditioning the withdrawn CSF; and    -   e) returning the conditioned CSF to the ventricle through the        other of said ports.

With respect to the embodiments of the methods, in some embodiments, theCSF is removed or withdrawn and returned at substantially the same flowrate. In some embodiments, the CSF is removed or withdrawn and returnedat the same flow rate. In some embodiments, the flow rate is in therange from about 0.04 ml/min to about 30 ml/min, for example, from about5 ml/min to about 20 ml/min, for example, about 1, 2, 3, 5, 7, 10, 12,15, 18 or 20 ml/min.

In some embodiments, the volume of CSF removed is below the volume thatwould induce a spinal headache or symptoms of overdrainage. In someembodiments, the volume of CSF removed from the patient never exceedsabout 35-45 ml, for example, about 40 ml, 35 ml, 30 ml or 25 ml.

In some embodiments, the distance between the first location and thesecond location is at least about 4 cm, for example, about 5, 10, 20,25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90 or 100 cm. In someembodiments, the distance between the first location and the secondlocation is separated by at least about 2 vertebrae.

In some embodiments, the first location or the proximal port is atsacral Si or lumbar L5 or above and the second location is at lumbar L3or above. In some embodiments, the first location or proximal port is atS1, L5, L4, L3, L2, L1 or above. In some embodiments, the secondlocation or distal port is in the sacral, lumbar, thoracic or cervicalCSF space. In some embodiments, the second location or distal port is inone or more ventricles. In some embodiments, the second location ordistal port is in the cranial subarachnoid space.

In some embodiments, the first location or proximal port is in thecranial subarachnoid space. In some embodiments, the first location orproximal port is in one or more ventricles. In some embodiments, thesecond location or distal port is in the lumbar, thoracic or cervicalCSF space. In some embodiments, the second location or distal port is inthe lumbar CSF space, for example at S1, L5, L4, L3, L2, L1 or above.

In some embodiments, the first location or proximal port and the secondlocation or distal port is in the ventricular space. For example, boththe first location or proximal port and the second location or distalport can on opposite sides of one ventricle. In another example, thefirst location or proximal port is in a first ventricle and the secondlocation or distal port is in a second ventricle.

In some embodiments, the distance between the first location or proximalport and the second location or distal port is adjustable. For example,a pair of tubular members in a multilumen catheter can be axiallyadjusted relative to one another.

In some embodiments, the flow directions of removing or withdrawing andreturning CSF are periodically reversed so that CSF is returned to thefirst location and removed from a second location during a portion ofthe treatment. For example, the flow reversal is a pulse to dislodgedebris from removal or return ports.

In some embodiments, the methods further comprise the step of mixing theconditioned CSF with unconditioned CSF as the conditioned CSF isreturned to the CSF space. In some embodiments, the methods compriseinducing a turbulent flow as the conditioned CSF is returned whichenhances mixing. For example, the turbulent flow can be created byintroducing a multilumen catheter comprising one or more helical flowpaths, textured (e.g., ribbed or bumped) flow paths, a T-separated flowpath, bellows, balloons, fins, and/or multiple exit ports (e.g., sideholes or side vents). Turbulent flow can also be induced by highpressure injection (i.e., “jetting”) or directed outflow.

In some embodiments, the conditioning comprises removing a targetedmolecule (e.g., protein, peptide, oligopeptide) from the CSF. Forexample, the conditioning can comprise one or more separation processesselected from the group consisting of biospecific affinity (e.g.,antibodies, nucleic acids, receptors, enzymes), immunoaffinity, cationicexchange, anionic exchange, hydrophobicity and various size exclusionthresholds.

In some embodiments, the methods further comprise the step of isolatingthe targeted molecule.

In some embodiments, the conditioning comprises removing pathologicalcells (e.g., B-cell, T-cells, macrophages, erythrocytes and other bloodcells) and cellular debris.

In some embodiments, the conditioning step is performed externally tothe patient's body. In some embodiments, the conditioning step isperformed using a conditioning unit implanted in the patient's body.

In some embodiments, the catheter apparatus consists essentially of asingle catheter body having a lumen connected to the distal port and aseparate lumen connected to the proximal port.

In some embodiments, the methods comprise ameliorating the symptoms ofAlzheimer's Disease in a patient by removing at least one ofbeta-amyloid or tau proteins from CSF employing the methods and systemsdescribed above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofParkinson's Disease in a patient by removing at least one ofalpha-synuclein proteins (including peptides or oligomers) from CSFemploying the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofAmyotrophic Lateral Sclerosis (ALS) in a patient by removing at leastone of insoluble superoxide dismutase-1 (SOD1), glutamate, neurofilamentprotein, and anti-GM1 ganglioside antibodies from CSF employing themethods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofcerebral vasospasm in a patient by removing at least one of blood cells(e.g., erythrocytes), oxyhemoglobin and endothelin from CSF employingthe methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofencephalitis in a patient by removing at least one of the causativebacterial or viral entity, tumor necrosis factor-alpha (TNFa) and IgGfrom CSF employing the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofGuillain Barre Syndrome (GB S) in a patient by removing at least one ofcells and inflammatory mediators including but not limited to C5a, TNFa, IL 2, IL-6, interferon-y, IgG, and endotoxins from CSF employing themethods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofMultiple Sclerosis (MS) in a patient by removing at least one of Tcells, B cells, anti-myelin antibodies and inflammatory mediatorsincluding but not limited to TNF a, IL 2, IL-6, interferon-y from CSFemploying the methods and systems described above and herein.

In some embodiments, the methods comprise ameliorating the symptoms ofstroke in a patient by removing inflammatory mediators including but notlimited to endothelin and enolase and cooling the CSF (and hence theCNS), employing the methods and systems described above and herein.

In a related aspect, the methods provide systems for conditioningcerebrospinal fluid (CSF) in a patient. In some embodiments, the systemscomprise

-   -   i) a catheter assembly having a first lumen with a distal port        and a second lumen with a proximal port, said catheter being        adapted to be introduced in a CSF space and said ports being        spaced axially apart;    -   ii) a pump connectable between the first and second lumens to        induce a flow of CSF therebetween; and    -   iii) a conditioning component connectable between the first and        second lumens to condition the CSF flowing therebetween.

With respect to the embodiments of the systems, in some embodiments, thecatheter assembly consists essentially of a single tubular member havingthe first lumen and distal port and the second lumen and proximal portfixedly disposed therein.

In some embodiments, the catheter comprises a first tubular memberhaving the first lumen and the distal port therein and a second tubularmember having the second lumen and proximal port therein.

In some embodiments, the first and second tubes can be axiallytranslated relative to each other to adjust the distance therebetween.

In some embodiments, the pump has a flow rate adjustable between about0.04 ml/min to about 30 ml/min, for example, from about 5 ml/min toabout 20 ml/min, for example, about 1, 2, 3, 5, 7, 10, 12, 15, 18 or 20ml/min. In some embodiments, the pump comprises a peristaltic pump whichis isolated from the CSF flow. In some embodiments, the pump isimplantable (e.g., an Archimedes screw).

In some embodiments, the conditioning component is selected from thegroup consisting of biospecific affinity, immunoaffinity, cationicexchange, anionic exchange, hydrophobicity and size exclusion. Forexample, the conditioning component can be a column or a cartridge. Insome embodiments, the catheter comprises the conditioning component(e.g., bound to the inner surface of the catheter by covalent ornon-covalent bonding).

With respect to size exclusion and filtration, the filtration componentcan be any type, e.g., membranous, nanoparticular, flat, tubular orcapillary.

In some embodiments, the system has a CSF retention volume below about40 ml, for example, below about 35, 30, 25 or 20 ml.

In some embodiments, the system is implantable. In some embodiments, thesystem is partially external.

Definitions

The term “patient” refers to any mammal. The mammal can be a non-humanmammal, a non-human primate or a human. In some embodiments, the mammalis a domestic animal (e.g., canine, feline, rodentia, etc.), anagricultural mammal (e.g., bovine, ovine, equine, porcine) or alaboratory mammal (rodentia, rattus, murine, lagomorpha, hamster).

The term “CSF space” refers to any volume of cerebrospinal fluid foundin the cranial or spinal areas that is in contact with any component ofthe nervous system, but not within the tissue. Interstitial fluidresides in the tissue.

The phrase “conditioning CSF” or “conditioned CSF” interchangeably referto CSF wherein one or more target compounds have been partially, mostlyor entirely removed.

The phrase “consisting essentially of refers to the elements recited inthe claim as well as insubstantial elements, and excludes elements thatmaterially change the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a sagittal cross-section through the brain and spinalcord and illustrates the location of the choroid plexus and the passiveflow of CSF through the CNS. The inset depicts the arachnid granulationslocated along the major venous sinuses, which are the primary locationsfor CSF reabsorption.

FIGS. 2A, 2B, 2C, and 2D provide views of the ventricular system fromthe A) lateral surface, B) anterior surface, C) superior surface and D)detailed ventricular structure.

FIG. 3 illustrates the ventricular anatomy of the brain in a 3dimensional perspective.

FIGS. 4A, 4B, 4C, and 4D depict the Blood-Brain and Blood-CSF Barriers.A) fenestrated capillary allowing passage of water and solutes, B) braincapillaries with tight junctions between endothelial cells, formingblood-brain barrier; requires cellular transport, C) choroids plexusepithelial cells form the blood-CSF barrier and allow water and solutesbut require cellular transport, D) arachnid villi allow one-way bulkflow of CSF into major venous sinuses.

FIG. 5 illustrates the oligomeric hypothesis of neurodegenerativediseases. The multi-step process is thought to underlie a number ofdifferent neurologic conditions. The disease specific proteins undergo aspecific biochemical modification which makes them prone to join andform globular intermediates (known as oligomers). These oligomers arethought to be toxic and can continue to build on one another formingprotofibrils and fibrils. The fibrils may then be isolated into anintracellular inclusion (e.g. tau tangles) or an extracellular deposit(e.g. AP plaque) in the case of Alzheimer's disease.

FIG. 6A illustrates a schematic of the ventricular, spinal andventriculo-spinal approaches for accessing the CSF space for theefficient turnover of conditioned CSF. FIG. 6B illustrates oneembodiment of the dual- and single-ventricular approaches of theinvention. FIG. 6C illustrates one embodiment of the spinal approach ofthe invention.

FIG. 7 illustrates a schematic of a single lumen system. A single-lumensystem creates a local eddy (shading) with minimal mixing or access tocranial CSF.

FIG. 8A illustrates a schematic of a dual lumen system of the invention.A multi-lumen system creates an active and dynamic flow with efficientmixing that is not limited by pressure volume as inflow and outflow arerelatively equal. This allows for parallel processing of CSF withmaximum turnover and provides access to the cranial and spinal space andentire CSF volume (mixing represented by shading). FIG. 8B illustratesthe dramatic difference in CSF clearance produced with a multilumensystem in which inflow and outflow are substantially apart (line D),adjacent (line C) compared to a single lumen system (line B) compared todiffusion-limited flow (line A). FIG. 8C illustrates the effect ofcatheter inflow/outflow distance on the rate of reprocessing ofconditioned CSF.

FIGS. 9A and 9B illustrates cross-sections of sample dual or multilumencatheters, respectively, for use in the CSF space. These are but twoexamples of many embodiments that may be envisioned to achieve one ofthe ultimate goals of the invention which is a method to provideefficient mixing and turnover of CSF.

FIGS. 10A and 10B illustrate catheters with helical out flow paths whichinduce additional mixing at various outflow points. FIG. 10A illustratesa single helical outflow path over last length (l) of catheter. Astraight outflow lumen connects to the helical path. The cathetercomprises a straight central inflow lumen. FIG. 10B illustrates a dualhelical outflow path catheter with central inflow path.

FIG. 11A illustrates dual helical outflow paths exiting at differentpoints along the catheter. The catheter comprises a single centralinflow path. As described herein, the paths can be reversed, forexample, by a pump mechanism. Therefore, a catheter with a single inflowpath and multiple outflow paths could become a single outflow path withmultiple inflow paths. FIG. 11B illustrates how helical path directionalchanges as another means of creating a directed flow.

FIG. 12A illustrates two catheters bound by a double collar. The collaris fixed to one catheter and slips on other such that the distance “d”between the two ends is adjustable. In this case, the inflow catheter isinterfaced with the slipping portion of the collar. FIG. 12B illustratesa dual lumen catheter that is encircled by a tight fitting thin walledcannula. The outflow lumen of the inner catheter has side ports suchthat, as the cannula is pulled back additional side ports or openingsare exposed, thereby increasing the distance between the inflow andoutflow.

FIG. 13A illustrates a dual lumen catheter with addressable holes on onelumen. FIG. 13B illustrates a two catheter system creating a dual lumencatheter. As shown, the outflow catheter is created by the space betweenthe inner and outer catheters.

FIG. 14A illustrates a dual lumen catheter with partially overlappingside ports for use in sub arachnid to ventricular access. The holessurrounded by parenchyma would be sealed by the parenchyma. These wouldinclude the overlapping portion. FIG. 14B illustrates a close-up of anend showing one overlapping hole on the left. FIG. 14C illustrates amiddle section showing overlapping holes.

FIG. 15A illustrates an end section. FIG. 15B illustrates a catheterincorporating multiple balloons. The inflow and outflow lumens are seenon either side of the base “T-section.” The balloon inflation lumen isabove the T-section. The three balloon inflation ports can be seen fromthe top through thin membranes which form the balloons. FIG. 15Cillustrates a cross-section of an end with inflow and balloon inflationlumens visible along with an inflation port.

FIGS. 16A-C illustrate balloons inflated. A catheter can contain singleor multiple balloons. The balloons can be spherical or long. Longslender balloons are well-suited for a spinal column space. The distancebetween balloons can be uniform or of different lengths.

DETAILED DESCRIPTION OF THE INVENTION 1. Introduction

The present invention provides methods, devices and systems forremoving, detecting, returning and delivering compounds from and/or to apatient's cerebrospinal fluid (CSF) space. The removal and/or deliveryof specific compounds can be tailored to the pathology of the specificdisease. The removal is targeted and specific, for example, through theuse of specific size-exclusion thresholds, antibodies against specifictoxins, and other chromatographic techniques, as well as delivery and/orremoval of targeted therapeutic agents. The invention finds use as adiagnostic, therapeutic and drug delivery platform for a variety ofdiseases affecting the CNS by accessing the CSF space.

For the first time, the present invention offers a targeted, focused andlogical treatment platform to treat a variety of debilitating and oftendevastating neurological diseases to which there are presently limitedand ineffective treatment options. Exemplified disease conditionstreatable by the present CSF processing systems and methods include, butare not limited to: Cerebral Vasospasm, Guillain Bane Syndrome,Alzheimer's, Parkinson's, Huntington's, Multiple Sclerosis, AmyotrophicLateral sclerosis, Spinal Cord Injury, Traumatic Brain Injury, Stroke,Cancer affecting the brain or spinal cord, Prion disease, Encephalitisfrom various causes, Meningitis from various causes, diseases secondaryto enzymatic or metabolic imbalances, Biological Warfare, etc. For thefirst time, the present invention offers patients a disease-modifying,disruptive technology that addresses the known disease pathogenesis andeffectively ameliorates the symptoms of a number of neurologicconditions.

CSF: Cerebrospinal fluid (CSF) is primarily produced by the human CNS byvascular plexuses termed choroid plexus in the lateral third, andfourth, ventricles of the brain (FIG. 1). This normally clear, wateryfluid maintains a gradient between it and the interstitial fluid of thenervous system. Water and soluble substances are freely exchangeablebetween the CSF and the nervous system. Thus, many neurotransmitters,peptides and other neuroactive substances can be found within the CSF.The functional role of many of these peptides is under current research.The concentration of various neuroactive substances in the CSF is ofgreat interest, because it represents an indirect view that correspondsclosely to the extracellular fluid in the immediate vicinity of theneurons in the brain and spinal cord. Thus, CSF serves two mainfunctions: 1) by coating the brain and spinal cord it provides aprotective function, providing buoyancy and preventing traction onvessels and nerves upon impact to the skull or spinal column; 2) perhapseven more importantly, it contributes the maintenance of a constantcomposition of the neuronal environment. See, Blumenfeld, H. (2002).“Neuroanatomy through Clinical Cases.” 951.

Neuroanatomy/Flow: In healthy adults, CSF is produced at a rate of about0.3 ml/min, 18 ml/hour, or about 432 ml/day. However, the total volumefound in the ventricles and subarachnoid space is about 150 ml (FIGS.2A-2D). Thus, the total volume of CSF is turned over several(approximately three) times each day. The fluid produced in the lateralventricles flows via the intraventricular foramen (of Monroe) into thethird ventricle, then via the narrow cerebral aqueduct into the fourthventricle (FIG. 3). From there, it exits via the midline posteriorly(foramen of Magendie) or laterally (foramen of Luschka) (FIG. 2D). TheCSF then spreads over the entire surface of the brain and spinal cord,providing a constant balance of extracellular fluid to individualneurons throughout the CNS. The CSF is drained by small protrusionscalled arachnid granulations, which are particularly prominent along themajor venous drainage sites such as the superior sagittal sinus (FIG. 1,inset). Fluid passes from the subarachnoid space to the venous sinusesby a hydrostatic gradient. Some of the CSF is also drained via otherroutes, such as lymphatic vessels along cranial and spinal nerves. See,Blumenfeld, H. (2002). “Neuroanatomy through Clinical Cases.” 951.

Barriers: In most organs, small-molecular weight substances pass thecapillary wall with relative ease, and their concentration is thereforesimilar in the plasma as in the interstitial (extracellular) fluid. Thecomposition of the interstitial fluid of the CNS differs from most otherorgans because of the selective properties of brain capillaries, knownas the blood-brain barrier (BBB). This barrier is comprised of extensivetight junctions between endothelial cells, preventing the passage of anumber of substances from the peripheral plasma (FIGS. 4A-4D). Similarto the BBB, the epithelium of the choroid plexus represents anadditional barrier between blood and CSF, known as the blood-CSFbarrier. Thus, many substances that can leave the capillaries of thechoroid plexus cannot enter the CSF. Neurons depend on the precisecontrol of ions and compounds in their extracellular environment fortheir normal functioning. See, Blumenfeld, H. (2002). “Neuroanatomythrough Clinical Cases.” 951.

Neurologic Diseases: Diseases affecting the nervous system are among themost devastating and debilitating medical conditions. Increasingly weunderstand the pathophysiology of a variety of endogenous and exogenouspathogens that can be found within the CSF that produce a direct orindirect deleterious effect on the CNS. This represents an opportunityfor intervention and prevention or amelioration of the disease process.Furthermore, the system can be tailored to the individual diseaseprocess in a logical, targeted and focused manner.

The concept that numerous distinct disorders of the brain and spinalcord would require a different, disease-specific therapeuticintervention has been challenged by the discovery that several of thedisorders have common underlying disease mechanisms. This provides anopportunity for intervention with a device platform that addresses anumber of different diseases based on a few fundamental conceptsinvolving the purification and modification of CSF based on size,biologic components and temperature.

It is now understood that a number of “endogenous pathogens” (neurotoxicmolecules released from the brain into the CSF) and “exogenouspathogens” (cells and neurotoxic molecules from the peripheralcirculation which enter the CSF) can perturb the normal environment ofthe CNS and are thought to play a key role in a number of diseasesaffecting the nervous system. See, Caughey, B. and P. T. Lansbury(2003). Annu Rev Neurosci 26: 267-98.

Many neurodegenerative disorders are characterized by aggregates ofprotein fibrils and neurotoxic oligomeric species and infiltrations ofpathological inflammatory cell types (e.g., B-cells, T-cells,macrophages) that are implicated in progressive brain degeneration. See,Caughey, B. and P. T. Lansbury (2003). Annu Rev Neurosci 26: 267-98; andTaylor, J. P., J. Hardy, et al. (2002). Science 296(5575): 1991-5. See,Table 1 and FIG. 5. Despite differences in the molecular composition ofthese protein fibrils as well as the brain regions and cell typesaffected in each disorder, these diseases share a similar pathologicalmechanism and therefore, they share similar mechanisms of treatment froma medical device point of view.

TABLE 1 Current US Current Current US Prevalence Proteinacious AbnormalMedical Cost/Year Disorder (persons) Deposit Protein Treatment(billions) Alzheimer's ~4 million Senile plaques Aβ acetylcholinesterase$100 Disease (AD) ~22 million and oligomers inhibitors by 2025neurofibrillary Tau tangles oligomers Parkinson's ~1 million Lewy bodiesa- synuclein L-dopamine $25 Disease (PD) oligomers Multiple ~350,000Demyelinating Anti- interferon-β $10 Sclerosis (MS) Plaques myelinantibodies Huntington's ~30,000 Intraneuronal Huntingtin none $2.5Disease (HD) Inclusions oligomers Amyotrophic ~30,000 IntraneuronalInsoluble glutamate $1 Lateral inclusions SOD1 release Sclerosis (ALS)inhibitors

Immunotherapy: Recently, the immunological concept in the treatment ofconformational diseases has gained more attention and immunizationapproaches are being pursued in order to stimulate clearance, forexample in Alzheimer's Disease (AD), of brain beta-amyloid protein (AP)plaques. They include both active and passive immunization techniques.Active immunization approaches employ various routes of administration,types of adjuvants, the use of modified AP epitopes and/or immunogenicAP conjugates. See, Morgan, D., D. M. Diamond, et al. (2000). Nature408(6815): 982-5. Passive immunization approaches include monoclonalantibodies or specific antibody fractions (Fabs) directed againstspecific AP epitopes. See, Monsonego, A. and H. L. Weiner (2003).Science 302(5646): 834-8. Plaque clearance as a result of immunotherapymay depend on multiple mechanisms. One theory involves directinteraction of antibodies, or Fab fragments, with the deposits resultingin disaggregation and microglial cell-mediated clearance. A secondtheory involves antibodies acting as a sink for AP peptide, removing itfrom the CNS and preventing plaque deposition in the brain by passiveredistribution of soluble Aβ oligomers between brain, CSF, and plasmadown a concentration gradient. See, Roberson, E. D. and L. Mucke (2006).Science 314(5800): 781-4. Significant data from animal studies exists tosupport both mechanisms with a substantially reduced A burden in thetransgenic mouse model along with improvement in memory disturbances.See, Janus, C., J. Pearson, et al. (2000). Nature 408(6815): 979-82.Promising evidence from A immunization in transgenic mice showingclearance of A plaques and improvement in cognitive disturbances, led tohuman clinical trials. Unfortunately, human patients actively immunizedwith an A immunogen developed signs of meningoencephalitis as aconsequence of active immunotherapy. See, Orgogozo, J. M., S. Gilman, etal. (2003). Neurology 61(1): 46-54; Bayer, A. J., R. Bullock, et al.(2005). Neurology 64(1): 94-101; and Gilman, S., M. Koller, et al.(2005). Neurology 64(9): 1553-62. Human patients passively immunizedwith antibodies against the A protein developed neutralizing endogenousantibodies against the anti-A antibodies, nullifying the therapeuticeffect of the passive immunotherapy, and also potentially resulting in adetrimental increase in A protein. See, Hock, C., U. Konietzko, et al.(2003). Neuron 38(4): 547-54; Nicoll, J. A., E. Barton, et al. (2006). JNeuropathol Exp Neurol 65(11): 1040-8; and Melnikova, I. (2007). Nat RevDrug Discov 6(5): 341-2.

The primary concerns with both active and passive immunization lie inthe pro-inflammatory consequences following immunization, which may leadto overactivation of microglia. In addition to the multiple inflammatorypathways thought to be involved in AD there are particular inflammatorypathways that are activated specifically following microglialstimulation, including release of proteases and cytokines, andactivation of the oxidative burst that may exacerbate brain inflammationand AD-related neurodegeneration in the process of scavenging A. Inaddition to inflammation, concerns exist for development ofauto-antibodies with immune tolerance and the inability to reverse thetreatment once administered. Furthermore, for redistribution of solubleA oligomers down the brain, CSF plasma concentration gradient, it isunknown whether A is degraded in the plasma or taken up by specificorgans. To address these concerns, one needs a therapy that preventsantibody from entering the CNS while still sequestering the toxicprotein of interest.

The CSF Purification system described in the present invention serves asa broad platform technology for the treatment of a number of diseasesaffecting the nervous system. Several examples along with detailedrationale are provided below for a number of neurologic diseases towhich there are presently limited or ineffective therapies.

It would be desirable to provide improved and alternative methods,systems, kits for the processing, purification and/or modification ofCSF for a variety of purposes. The current invention possesses numerousbenefits and advantages over previously described methods. First, theremoval of agents based on size (such as red blood cells and theirbreakdown products in cerebral vasospasm, T- and B-cells in MS,auto-antibodies in GBS). With the recent advances in nanotechnology andultrafiltration, it is now possible to remove agents on the nanometerscale as opposed to micrometer, nearly a 1000.times. improvement intargeted filtration than previous systems. Prior filtration methodsbased on size were limited to 0.2 micron filters allowing the majorityof smaller toxic molecules to pass directly through the filter and backto the patient.

Second, with the recent advances in immunotherapy, the current inventionapplies ex-vivo immunotherapy targeted at removal of pathogenicmolecules from the CSF that directly affect the CNS. Antibodies providean unprecedented level of specificity to molecules that are too small toremove by present-day size filters. In vivo immunotherapy applicationshave been met with a number of serious complications includingencephalitis and death as described above. By securing the antibody toan immunoaffinity column, for example using a streptavidin-biotin system(strongest chemical bond known), CSF is processed over the antibodycartridge and sequestration of toxic oligomers and/or proteins can beachieved with no risk of systemic antibody delivery, encephalitis ordeath. The use of biologic separation (including Abeta and Tau proteinsin AD, alpha-synuclein in PD, etc.) can be beneficially applied to anumber of diseases by altering the neuro-immune axis using a platformex-vivo immunotherapy approach.

Third, modulation of temperature by mild, moderate or severe hypothermiahas been shown to have beneficial effects in terms of neuroprotection.Localized cooling of the CNS without systemic effects on the heart,liver or kidney may provide an added advantage in a number of diseasesincluding stroke, traumatic brain injury and spinal cord injury. Suchobjectives are met by the invention described hereinafter.

1. Systems of the Invention

The CSF purification system includes a multi-lumen catheterincorporating two or more lumens for the efficient exchange of CSF fromeither cranial and/or spinal CSF spaces. The present system creates adynamic circulation with significant mixing within the cranial or spinalCSF space. The present invention allows for the processing of largevolumes of CSF in a short amount of time while minimally impacting theendogenous intracranial/intraspinal pressure and volume.

The purification (or compound removal) schema can be tailored to aspecific disease or group of diseases based on a number of features,including size, affinity, biochemical properties and/or temperature, butmore specifically purification schema based on diffusion,size-exclusion, ex-vivo immunotherapy using immobilized antibodies orantibody fragments, hydrophobic/hydrophilic, anionic/cationic, high/lowbinding affinity, chelators, anti-bacterial, anti-viral,anti-DNA/RNA/amino acid, enzymatic, magnetic or nanoparticle-basedsystems. The system allows for passive flow but also includes amechanism of active pumping with transient or continuous flow such thatinflow and outflow are relatively equal to one another. Furthermore, anumber of safety measures (including, but not limited to, pressuresensor, velocity detector, bubble detector, pH, temperature, osmoticequilibrium, blood pressure, transmembrane pressure sensor) to ensurepatient safety are included. Pressure sensors to continuouslyrecord/maintain/adjust intracranial and/or intraspinal pressures arealso available. Programmable control of intake, output and overflowexhaust valves are additional contemplated features. The system isadjustable to a broad range of biologic parameters and flows. Alarms andautomatic on/off settings are further included to provide a signal forimmediate attention and interrogation of the system. A given volume ofCSF is outside the patient at any one time, less than that whichproduces symptoms associated with spinal headache or overdrainage.

Accordingly, the CSF purification/conditioning systems provide adual/multi-lumen catheter design. Flow studies have indicated that adual or multilumen catheter with inflow and outflow separated from oneanother by an appropriate distance serves to create and maintain adynamic circulation and efficient mixing/exchange of CSF. Given thenormally occurring variations in patient anatomy, such a distance mayvary by individual. Therefore a system which allows for the variation inthis distance in situ or prior to application (i.e., implant) wouldprovide a further improvement in performance for such systems in thereapplication across the population. The flow dynamics created with such asystem are dramatically different than a single lumen system or a systemwhere the inflow and outflow points are closely spatially located (FIG.7). Dye studies clearly demonstrate that the present systemincorporating catheters with dual or multilumen designs and spaced apartinputs and outputs allow for a greater turnover of unprocessed CSF perminute, or more efficiency with minimum mixing of unprocessed andprocessed CSF, thereby accessing a significantly larger portion of theentire CSF volume in a shorter period of time (FIG. 8A). The presentsystem design has dramatic effects on CSF physiology and flow. In thepresent dual lumen system, the distance of separation of inflow andoutflow sites determines the maximum “column of CSF” that can beprocessed and cleared initially (FIG. 8B). The catheter system with twoor more lumens as well as multiple holes for inflow and outflow alongthe length of the catheter not only minimizes clogging but providesgreatly increased turnover and access to the basal cistern, ventricular,cranial as well as spinal subarachnoid CSF than previously describedanywhere in the literature. The greater efficiency at removing compoundsof interest arises from less reprocessing of the same fluid (FIG. 8C).

Simple single lumen catheter systems produce only a local eddy, withminimal mixing and therefore recirculation of much of the same,previously processed CSF. Such single lumen systems do not generateenough mixing to adequately draw or circulate fluid from the cranial CSFspace that bathes the brain. In vitro studies indicate that the rate ofmixing, the amount of new CSF turned over per minute as well as theaccess provided to turning over the cranial and spinal CSF volumemultiple times using the present invention results in a much more rapid,efficient and feasible CSF processing system that provides access to theentire CSF system than that attainable using a single lumen system. Thepresent invention provides the ability to run parallel removal andreturn flows as opposed to sequential. Furthermore, the multilumencatheter can also incorporate an adjustable distance between the inflowand outflow areas, providing additional freedom for creating mixing andcirculation of CSF (FIGS. 12A-12B).

Parallel or continuous processing of removal and return flows using themultilumen systems of the invention provides several advantages oversingle lumen systems that require sequential processing. First, parallelprocessing is more efficient and requires fewer steps than sequentialprocessing. Multilumen systems that provide for continuous, parallelprocessing also can be conveniently automated and are more suitable forimplantation. Because continuous, parallel processing systems can bedesigned to be closed, there is less need for human or manualintervention and better control of sterility. Moreover, continuous flowprocessing is not limited by the volume limitation on the amountprocessed; a wide range of flow rates and volume exchange can beaccomplished (FIGS. 9A-9B). The only limitation is the dead space volumeof the tubing, particularly in partially external systems.

The shape of the lumens is also a factor to consider. Studies have shownthat simple circular lumens are more prone to clogging and necessitatingrepeated irrigation and/or catheter replacement. The dual/multi-lumencatheter systems described herein include a plurality of designsincluding, but not limited to, a combination of variable size andorientations of circular, oval, square, etc. designs to avoid catheterclogging. A combination of transient and/or continuous flow facilitatesthe maintenance of lumen patency and significantly decreases the risk ofclogging associated with present day systems. The dual or multilumensystem also allows for reversal of flow and rapid unclogging byintermittent reversal of flow by the pumping system. A dual lumen systemprovides the further advantage of allowing increased time periods in aparticular flow direction by moving the clogging agents further awayfrom the input.

The distal portion of the catheter can be constructed to promote maximalmixing and exchange of returned and unconditioned CSF upon return of theconditioned CSF. The elements that enhance mixing can be external orinternal to a patient's body. One example is a helical or double helicaldesign (i.e., FIGS. 10A-10B), with or without bellows, to create maximumdisruption/turbulence of passive CSF flow and more complete mixing andexchange of endogenous for processed CSF. Other examples include usingjetting or directing outflow such that eddies or turbulence are createdand thereby enhance mixing (FIGS. 11A-11B).

The catheter can contain a number of distal geometries to enhance mixingand exchange of CSF. One example is a T-catheter lumbar design (i.e.,FIGS. 13 and 15) in which both entry and exit lumens are inserted as asingle catheter and the distal lumen either folds away or is deployedusing a release mechanism such that one maximizes the distance betweeninflow and outflow sites and makes maximal surface area contact with theCSF space. Another example is the addition of small fins, a nonplanarsurface, ribbed portions or a small balloon system (i.e., FIGS. 15 and16) anywhere along the length of a cranial or spinal catheter thatcreates further mixing and exchange of endogenous and processed CSF.Examples of catheter designs that promote flow turbulence and mixing areshown in FIGS. 10A-16.

A portion of the purification system can be incorporated into thecatheter itself by fashioning it with a membrane that allows for thepassive filtration of the endogenous CSF and/or equilibration with theprocessed CSF.

In some embodiments, the catheter includes radio-opaque markers for theaccurate localization and confirmation of catheter tip location in thecranial or spinal CSF spaces. The radio-opaque markers can then bevisualized using simple X-ray or computerized tomography. A variety ofother methods can be utilized to confirm accurate catheter deploymentand placement. This includes the use of an endoscope to directlyvisualize placement of the cranial or spinal catheter. This method mayespecially be useful in those patients with small cranial ventriclescontaining CSF or in those patients with spinal stenosis or scoliosis,where lumbar access is challenging.

One of the major concerns of any implanted device is the risk forinfection. The risk of infection in the CSF is serious and includesmeningitis, encephalitis and even death. A number of safety measures canbe incorporated into the present invention to minimize and/or eliminatethe possible risk of patient infection. First, the proximal end of thecatheter can be tunneled a variable distance away from the entry site tominimize the risk of organisms tracking back in from the skin surfaceentry site. Second, meticulous care on a daily basis to clean the siteof catheter access can be performed by a nurse or taught to the patient.Third, immediately before catheter placement as well as during the timethe catheter remains indwelling during CSF processing and immediatelyafter removal, antibiotics can be administered to the patient to furtherreduce the risk of infection. Fourth, the catheter system itself can beimpregnated with a specific antibiotic of choice. Fifth, a specificmetal that can produce a transiently charged surface, which has beenshown to deter bacterial ingrowth and the incidence of catheterinfections in general, can be incorporated. Sixth, an antibiotic ofchoice can be delivered into the CSF a certain time before, during orafter CSF processing to further eliminate the risk of bacterial seedingor infection. Finally, an antibiotic cuff at one or more places alongthe catheter system can be placed to further reduce any risk ofinfection.

Another concern of any catheter system is the risk of kinking orphysical obstruction. The current invention incorporates a number ofsafety sensors to ensure that inflow and outflow are generallyrelatively equal. However, in addition, incorporating certain shapememory alloys in catheters (for example, in one of the lumens of FIG.9B) for use in the CSF space can be an added strategy of preventingkinking, maintaining shape, and allowing for maximum access of the CSFspace. Nickel titanium is a shape memory alloy also commonly referred toas Nitinol. Above its transformation temperature, it is superelastic andable to withstand a large amount of deformation. Below itstransformation temperature, it displays a shape memory effect. When itis deformed, it will remain in that shape until heated above itstransformation temperature, at which time it will return to its originalshape. Nitinol is typically composed of about 55% nickel by weight andmaking small changes in the composition can change the transitiontemperature of the alloy significantly which makes it suitable for manyapplications in medicine. In some embodiments, the catheter incorporatesnickel titanium in its manufacturing. Such a catheter would allow forthe easy entry of the catheter via the cranial or spinal access routesdue to superelastic nature of Nitinol, while once in the CSF space thecatheter would be return to its prior structure due to its shape memory.Nitinol's physical function resembles biological muscle; when activatedit contracts. The contraction movement may be applied to any taskrequiring physical movement with low to moderate cycling speeds. Thesmall size, light weight, ease of use and silent operation allow it toeven replace small motors or solenoids. Such a catheter system that isinternally adjustable and tailored to access varying areas of thecranial or spinal CSF space while minimizing the risk of kinking andcatheter obstruction would be an additional feature in the presentinvention.

In some embodiments, the systems incorporate a conductive material orheat-exchange element into a portion of the catheter system (forexample, in one of the lumens of FIG. 9B) that would allow for the rapidand direct alteration of the CSF space for those disorders needing rapidadjustment of temperature. The neuroprotective effect of profoundhypothermia has long been recognized, but use of hypothermia for thetherapy of neuronal injuries was largely abandoned because of managementproblems and severe side effects, such as cardiac arrhythmia, shivering,infections, and coagulation disorders. In the past decade, it has cometo be recognized that mild (34° C. to 36° C.), moderate (34° C. to 28°C.) and severe (<28° C.) hypothermia allow for therapeutic modulation oftemperature and may substantially avert brain damage caused by ischemiain both experimental stroke and other neuronal injuries. After focalcerebral ischemia, hypothermia reduced infarct volumes up to 90% and hasbeen found to have significant beneficial effects on patients sufferingfrom traumatic brain injury or spinal cord injury. By contrast,hyperthermia has been shown to have a significantly negative effect onCNS histopathology and outcome.

Such a temperature adjustable cooling catheter designed specifically forthe cranial or spinal CSF space, which can be used independently or inconjunction with an extracorporeal refrigerant system described in theprior literature, provides an added mechanism of rapid and direct CNScooling without the systemic side effects seen on the heart orcoagulation cascade seen when cooling the entire blood volume. Such aCSF cooling system has multiple utilities, including but not limited to,stroke, traumatic brain injury (TBI), spinal cord injury (SCI) and canbe used separately or in conjunction with variouspurification/conditioning schema discussed above and herein. Temperaturesensors of endogenous as well as processed CSF in addition to systemicbody temperature can be incorporated into the heating/cooling system toappropriately record/maintain/adjust temperature.

The present systems allow for a number of different CSF inflow andoutflow connections for the processing of CSF between any point in theCSF system such that total inflow and outflow are relatively equal. Thespatial location of the inflow and outflow ports are sufficientlydistant to allow for CSF flow throughout a major portion or the entireCSF space. The custom cranial or spinal catheters can be introduced viaa number of routes, including but not limited to: single ventricularinsertion, dual ventricular insertion, single level spinal insertion,dual/multi-level spinal insertion and ventriculo-spinal. In someembodiments, a first catheter is inserted into a brain ventricle or intothe cervical spine, and a second catheter is inserted into the lumbarspine. In addition, any of the above systems could be fashioned toexchange CSF from any two points within the subarachnoid space. Oneexample is a ventricular catheter with entry/exit sites communicatingwith the subarachnoid space overlying the adjacent brain parenchyma.

The present systems allow for the active movement of a large volume ofCSF over time, and do not require the removal or diversion of CSF fromthe human body. Due to the varying entry and exit sites in the customcatheter, the system allows for the production of active, in addition tothe normally passive, CSF flow. The active movement of CSF can begenerated in a number of ways including but not limited to motorizedpumps for active CSF withdrawal and return. Furthermore, the pump systemcan have a variety of mechanisms which facilitate the requirement thatinflow and outflow are relatively equal. Examples of suitable pumpsinclude rotatory, syringe-driven, volumetric, peristaltic, piston,pneumatic, bellows, electromagnetic, magnetostrictive, hydraulic, andthe like. The pumps can be a single apparatus with bi-directionalfunctionality or two unidirectional pumps that are in communication withone another. There are several pumping mechanisms available to reach thedesired endpoint of creating active, in addition to the normallypassive, flow of CSF. The pump can be external or internal to thepatient's body. Internal or implantable pumps are known in the art(e.g., an Archimedes screw pump).

In some embodiments, the systems provide a customizable conditioningsystem based on the specific disease process being addressed. Removal ofspecific compounds can be targeted based on size-exclusion, specificantibodies, hydrophobic-hydrophilic interactions, anionic-cationicexchangers, compounds with high-low binding affinity, anti-bacterial,anti-viral, anti-DNA/RNA, immunotherapy-based, immuno-modulatory,enzymatic digestion, etc. In addition to the variety of neurochemicalfiltration approaches, other filtration systems based onelectromechanical basis including radiofrequency, electromagnetic,acoustic wave, piezoelectric, electrostatic, atomic force and ultrasonicfiltration can be employed. Other features can be added to the filtersystem including a differential centrifugal force to aid in the rapidseparation of items of interest, e.g. ultrafiltrate, proteins, cells,etc.

In some embodiments, a cartridge-based schema can be employed for rapidchanging or combinations of the aforementioned purification-basedschema. For example, a system combining size, antibody and charge basedapproaches is envisioned with a single or multiple cartridges for thepurification, such that when the time came for replacement of thepurification filter, antibody, etc., it could be done in an easy to use,rapid exchange system. The conditioning system or chromatographiccartridges (e.g., biospecific interaction, ionic exchangers, sizeexclusion) can be external or internal to a patient's body. In someembodiments, the conditioning cartridges or filters are contained withinone or more lumens of the multilumen catheters. In some embodiments, thelumen of the catheters, or sections thereof, are coated (e.g., bycovalent or non-covalent binding) with chromatographic moieties (e.g.,biospecific capture moieties, including antibodies and nucleic acids,cationic or anionic exchangers, hydrophobic moieties, and the like).

In some embodiments, the systems include sensors for the intermittent orcontinuous monitoring and/or sampling of CSF levels of specificcompounds or parameters of interest. For instance, in cerebralvasospasm, one could serially sample and quantify levels of red bloodcells, hemogolobin, endothelin, or other molecules and have anindication of how much the system has cleared the CSF. Similarly inAlzheimer's, one could measure levels of A, Tau or other molecules andhave an indication of production or removal of specific items ofinterest. Sensors may be utilized to record/maintain/adjust levels ofspecific compounds in the CSF noninvasively.

1. Methods of Use

-   -   a. Methods for Conditioning Cerebrospinal Fluid

The invention provides for methods for conditioning cerebrospinal fluidin a patient using the systems of the invention. The cranial or spinalcatheters are placed using appropriate anatomic landmarks which areknown to those skilled in the art such that said custom catheter is incontact with the CSF space of interest. The cranial catheter is placedat specific points and trajectory such that one enters the ventricularCSF space or cranial subarachnoid space overlying the brain parenchyma.In the case of a spinal catheter, a cannula is placed at any point alongthe spinal canal (often lumbar) and provides a conduit for which toplace said custom spinal catheter into the CSF space. In particular, amulti-lumen spinal catheter can be inserted between a patient's lumbarvertebrae, for example, using a needle cannula to advance the catheter.In some embodiments, a sacral catheter is inserted in the sacral regionabove S1. In some embodiments, a lumbar catheter is inserted in thelumbar region above L5, L4, L3, L2 or L1. In other embodiments, a spinalcatheter is inserted between thoracic or cervical vertebrae. For bothspinal or cranial entry, the patient can be supine, sitting, or at anyangle between 0° and 90°.

CSF is removed from the cranial or spinal CSF space passed through adisease-specific conditioning system and returned to a differentlocation in the cranial or spinal CSF space. CSF is removed using acombination of natural passive flow but augmenting it with a pumpingmechanism to produce an active CSF flow dynamics. The volume of CSFoutside the body at any given time is less than that which would producea spinal headache or symptoms of overdrainage (about 40 ml). Thelocations of the catheter may vary but include single, multi-lumen or acombination of catheters placed via single ventricular insertion, dualventricular insertion, single level spinal insertion, dual/multi-levelspinal insertion and ventriculo-spinal.

One exemplification includes use of a single level spinal insertion thatis inserted in the lumbar space and fed cranially such that the cathetertip is in the cervical region. In this example, CSF inflow may be fromthe cervical portion and output from the lumbar portion and/or anywherealong the length of the multi-lumen catheter, depending on the numberand location of exit ports along the outflow lumen. In anotherembodiment, inflow can be at the lumbar region and outflow at thecervical, subarachnoid or ventricular regions. In another embodiment,both the inflow and outflow ports are in the ventricular space, forexample, with one port in a first ventricle and a second port in asecond ventricle. In another embodiment, the inflow and outflow portsare located at different sides of the same ventricle.

The flow rates may be varied and are limited by the pressuredifferential placed on the catheter walls, but generally can be in therange of 0.04 ml/min to 30 ml/min, for example, about 5 to 20 ml/min,for example, about 0.5, 1, 2, 5, 8, 10, 12, 15, 20 ml/min.

The CSF is then conditioned using a variety of mechanisms as describedabove and generally include size, biospecific and/ortemperature-mediated mechanisms. In performing the conditioning step,the removed or withdrawn CSF is contacted with one or more substratescomprising chromatographic, electrochemical or electromechanicalselection agents.

The methods provide a customizable conditioning schema based on thespecific disease process being addressed and the target compounds to beremoved from the CSF. Depending on the one or more target compounds tobe removed (e.g., proteins, oligomeric peptides, amino acids, nucleicacids, bacteria, etc.), the CSF can be contacted with one or moresubstrates comprising size-exclusion filtration, hydrophobic-hydrophilicinteractions, anionic-cationic exchangers, compounds with high-lowbinding affinity, anti-bacterial, anti-viral, bio specific interactionsincluding nucleic acid hybridization and immunoaffinity (e.g.,antibodies or non-antibody binding proteins), enzymatic digestion, or acombination thereof. Antibodies can be whole immunoglobulin molecules orfragments thereof (e.g., FAb, single chain variable regions (scFv),variable regions). Non-antibody binding molecules, for example, based onA-domain scaffolding, also find use. In addition to the variety ofchromatographic approaches, filtration systems based onelectromechanical bases also find use, including radiofrequency,electromagnetic, acoustic wave, piezoelectric, electrostatic, atomicforce and ultrasonic filtration can be employed. The CSF may also besubject to differential centrifugal force to aid in the rapid separationof items of interest, e.g. ultrafiltrate, proteins, cells, etc.

In some embodiments, the CSF is contacted with multiple substrates,e.g., combining size, bio specific and charge-based selection criteria.The conditioning step can be performed external or internal to apatient's body. In some embodiments, the conditioning substrates arecontained within one or more lumens of the multilumen catheters. In someembodiments, the lumen of the catheters, or sections thereof, is coated(e.g., by covalent or non-covalent binding) with chromatographicmoieties (e.g., biospecific capture moieties, including antibodies andnucleic acids, cationic or anionic exchangers, hydrophobic moieties, andthe like).

The concept of ex-vivo immunotherapy (i.e., immunoaffinity) using theCSF is itself a broadly applicable and novel component of the presentinvention. A number of conditions affecting the nervous system are nowbetter understood and a common feature is a disruption in theneuroimmune axis or weak points in the blood brain barrier allowingB-cells, T-cells and the humoral and cell-mediated immune responses. Inboth instances, the normal neuronal architecture is victim to a broadrange of neuro-inflammatory components and reactive oxidative stressproteins. The present invention allows for targeted removal ofinflammatory cells and proteins and elimination and/or neutralization ofoxidative stress proteins.

With regards to immunotherapy, present day active and passiveimmunotherapy treatments carry significant risk of encephalitis orgeneralized neuronal inflammation. By harnessing the immunotherapycomponents in an immobilized immunoaffinity approach, one can bring theCSF to the antibody and prevent any risk of mounting a generalizedimmune response against oneself. Furthermore, this eliminates the riskof autoantibodies against systemically delivered immunotherapies, whichcould have devastating effects and high mortality in a subset ofpatients. Cartridge-based schema would allow for further rapidreplacement of the conditioning approach.

The methods contemplate the periodic re-use or re-charging of thefiltration/processing component of the system. For instance, in theex-vivo immunotherapy approach, a specific eluent can be used to releasethe captured oligomers or proteins and regenerate the active antigenbinding sites on the antibodies. Furthermore, this eluted compoundrepresents a purified human protein which can then be used as a“neuropharmaceutical” agent. For example, in Alzheimer's disease,purified A or Tau components may then be released and used for a varietyof other commercial or research studies involving the structure-functionactivity of disease-specific compounds in human disease. Also, theability to automatically or periodically collect CSF or specificsubcomponents and store/freeze creating a CSF bank for specific diseaseprocesses is contemplated.

The conditioned endogenous CSF is then returned back to a CSF space in adifferent location than from which it was drawn. The second location ordistal port for outflow or output is at a sufficiently differentlocation from the first location or proximal port for inflow or input tocreate mixing of the conditioned and unconditioned CSF through amajority of the CSF space. For example at least about 50%, 60%, 70%,80%, 90% of the conditioned and unconditioned CSF in the CSF space canbe mixed. The inflow and outflow ports usually can be at least twovertebrae apart, for example, if both ports are in the spinal area. Inother embodiments, one of the inflow or outflow ports can be in thespine (e.g., sacral, lumbar, thoracic or cervical) and the other inflowor outflow port can be in the subarachnoid or ventricular space. In someembodiments, both the inflow and outflow ports are in the ventricularspace, for example, where the inflow port is in a first ventricle andthe outflow port is in a second ventricle (dual-ventricular embodiment).Depending on the design of the system, the quantitative distance betweenthe inflow and outflow ports can be at least about 4 cm, for example, atleast about 5 cm, 8 cm, 10 cm, 12 cm, 15 cm, 20 cm, 30 cm, 40 cm, 50 cm,or 60 cm, or longer, depending on the length of spine of an individualpatient.

As discussed above and herein, one or more different geometries in thedistal portion of the outflow lumen of the catheter facilitateturbulence mixing upon return of the conditioned CSF. For example, thedistal portion of the outflow lumen can be configured to be a single ordouble helical conformation, contain multiple exit ports (i.e., sideholes or vents), have textures surfaces that induce turbulence (e.g.,bumps, ribbing, etc.), have balloons, bellows, fins or turbines. AT-catheter configuration also finds use. The flow rate can also beincreased in the distal portion of the outflow lumen, e.g., by highpressure injection or jetting.

The removal or withdrawing steps and the return steps can be performedconcurrently, for parallel processing. This allows for a closed systemand continuous processing or conditioning of the CSF, the advantages ofwhich are described herein. Overall, the inflow and outflow rates can beequal or substantially equal. Active flow can be maintained using apump, as discussed above for the systems. The active flow rate can beuniform or discontinuous, as needed. Also, the flow path direction ofthe CSF can be reversed, periodically, intermittently, or throughout theduration of a treatment, such that the inflow port becomes the outflowport and the outflow port becomes the inflow port.

In addition to removal of specific toxins from the CSF, the presentmethods contemplate the delivery of therapeutic agents on the returncycle. That is, after a given volume is passed through the specificpurification schema of interest, a specific pharmacologic agent or drugcan be administered directly to the CNS and bypass the blood brainbarrier. This provides the opportunity for specific delivery ofpharmaceuticals to the CNS without the often many systemic side effectsassociated with oral or intravenous delivery. One of the challenges ofdrug delivery via the CSF is designing the drug to penetrate thebrain/spinal cord parenchyma. A variety of ways including adjusting thehydrophilicity or using liposome-based approaches in conjunction withthe system described herein may be envisioned. Thus, for the first time,the system described herein allows for the combined removal of specifictoxins as well as delivery of specific therapeutic agents to the CNS.

The present methods also contemplate the infusion of artificial CSFfluid into the system, if needed, at any time. The combined purificationof CSF with return of artificial CSF with appropriate physical/chemicalsafeguards in addition to the purified CSF is but one possibility. Thesystem may also be primed with such a physiologically compatibleartificial CSF solution.

a. Methods of Ameliorating Disease Conditions

i. Alzheimer's Disease (AD)

Alzheimer's disease (AD) is a progressive neurodegenerative disordercharacterized by abnormal accumulations of amyloid plaques andneurofibrillary tangles. Amyloid plaque formation is thought to bepartly due to failure of clearance of beta-amyloid protein (A). APP(amyloid precursor protein) generates various forms of amyloid A throughenzymatic processing. See, Blennow, K., M. J. de Leon, et al. (2006).Lancet 368(9533): 387-403. Diffusible oligomers of A (from plaques)inhibit long term potentiation, cause membrane damage, alter membranefluidity, and act as pore-forming toxins See, Caughey, B. and P. T.Lansbury (2003). Annu Rev Neurosci 26: 267-98; and Glabe, C. G. (2006).Neurobiol Aging 27(4): 570-5. In AD, tau proteins also aggregate,resulting in degeneration of neuronal axons and dendrites and producingneurofibrillary tangles. Tau protein accumulation leads to cellularoxidative stress, which may be a causal factor in tau-inducedneurodegeneration. See, Dias-Santagata, D., T. A. Fulga, et al. (2007).J Clin Invest 117(1): 236-45. Specifically, highly reactive oxygenspecies oxidize lipids, proteins, and DNA, leading to tissue damage andcell death. These markers for oxidized lipids and proteins accumulate inregions that are particularly affected in neurodegenerative diseases.Markers of oxidative damage have been detected in brain tissue frompatients with AD and other neurodegenerative disorders. See, Koo, E. H.,P. T. Lansbury, Jr., et al. (1999). Proc Natl Acad Sci USA 96(18):9989-90. Free radical injury also appears to be a fundamentalpathophysiologic mediator of tissue injury in human disease, includingacute ischemic stroke, amyotrophic lateral sclerosis, Parkinson'sdisease, and AD. See, Taylor, J. P., J. Hardy, et al. (2002). Science296(5575): 1991-5. Current therapies for AD are only marginallyeffective, as they may not slow rate of neurodegeneration, and havesignificant side-effects and some (immunization strategies) aretentative at best.

In contrast, CSF processing of amyloid and tau proteins andneutralization of reactive oxidative species among others is both asymptomatic and disease-modifying treatment through its ability toreduce, limit, and prevent plaque and tangle formation as well ascounteract neuroinflammation. It has the ability to address the diseaseprocess from multiple different perspectives based on our present dayunderstanding of disease pathogenesis. It may also be safer due to lowerrisk of liver damage and brain inflammation compared to currentpharmacologic and immunotherapeutic regimens, respectively.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of Alzheimer's disease by reducing or eliminating thepresence of beta-amyloid and/or tau proteins in the CSF using thesystems described herein. The methods comprise removing CSF from apatient, as described herein; removing at least one of pathologicalproteins, including A and tau, and inflammatory mediators (e.g.,cytokines, including TNF-a, IL-1, IL-2, IL-6, IL-12, interferon-y, etc.)from the CSF, and returning the endogenous CSF to the patient, whereinthe removing and returning steps are performed concurrently during atleast a portion of the treatment. In some embodiments, the A or tauproteins and/or inflammatory mediators are removed from the CSF using animmunoaffinity column or a size exclusion column, or both.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of Alzheimer's disease by introducing a catheter apparatusthrough a spinal access site into a spinal CSF space of a patient;advancing the catheter apparatus through the spinal CSF space craniallytoward the brain so that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one of A ortau proteins or inflammatory mediators from the withdrawn CSF therebyconditioning the CSF; and returning the conditioned CSF through theother of said ports.

Further embodiments for treating Alzheimer's disease are as discussedabove and herein.

i. Parkinson's Disease (PD)

Parkinson's disease (PD) is caused by a loss of dopamine-containingpigmented neurons in the substantia nigra. Free radical injury andformation of alpha-synuclein fibrils and oligomers (i.e., peptides) areinvolved in pathogenesis of PD. See, Steece-Collier, K., E. Manes, etal. (2002). Proc Natl Acad Sci USA 99(22): 13972-4. Current treatments(dopamine replacement therapy with L-dopa, Catechol-O-methyl transferase(COMT) inhibitors, amantadine and anticholinergic medications forsymptomatic relief, surgery with deep brain stimulation) do not have along-lasting effect, do not address the cause of disease and can havedebilitation side-effects including dyskinesias. See, Dunnett, S. B. andA. Bjorklund (1999). Nature 399 (6738 Suppl): A32-9; Dawson, T. M. andV. L. Dawson (2003). Science 302(5646): 819-22; and DeKosky, S. T. andK. Marek (2003). Science 302(5646): 830-4. There is a need for treatmentthat halts degeneration by removing free radicals and neurotoxicspecies. See, Shoulson, I. (1998). Science 282(5391): 1072-4. CSFfiltration has fulfills that unmet medical need and can represent adisease-modifying mechanism for new PD treatments.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of Parkinson's disease by reducing or eliminating thepresence of alpha-synuclein fibrils and/or oligomers in the CSF usingthe systems described herein. The methods comprise removing CSF from apatient, as described herein; removing at least one of alpha-synucleinproteins and inflammatory mediators from the CSF, and returning theendogenous CSF to the patient, wherein the removing and returning stepsare performed concurrently during at least a portion of the treatment.In some embodiments, the alpha-synuclein fibrils and oligomers areremoved from the CSF using an immunoaffinity column or a size exclusioncolumn, or both.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of Parkinson's disease by introducing a catheter apparatusthrough a spinal access site into a spinal CSF space of a patient;advancing the catheter apparatus through the spinal CSF space craniallytoward the brain such that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one ofalpha-synuclein proteins and inflammatory mediators from the withdrawnCSF thereby conditioning the CSF; and returning the conditioned CSFthrough the other of said ports.

Further embodiments for treating Parkinson's disease are as discussedabove and herein.

i. Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS)/Lou Gehrig's Disease is a rapidlyprogressive, invariably fatal motor neuron disease that attacks thenerve cells responsible for controlling voluntary muscles. See, Rowland,L. P. (1995). Proc Natl Acad Sci USA 92(5): 1251-3. Both the upper motorneurons and the lower motor neurons degenerate or die, ceasing to sendmessages to muscles. ALS patients had higher levels of glutamate in theserum and spinal fluid. Laboratory studies have demonstrated thatneurons begin to die off when they are exposed over long periods toexcessive amounts of glutamate. See, Rowland, L. P. (1995). Proc NatlAcad Sci USA 92(5): 1251-3. Increased levels of neurofilament proteinwere found in CSF of ALS patients as well as increased levels ofantibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides in20%, 15%, 8% of CSF of ALS patients, respectively. See, Valentine, J. S.and P. J. Hart (2003). Proc Natl Acad Sci USA 100(7): 3617-22; andBanci, L., I. Bertini, et al. (2007). Proc Natl Acad Sci USA 104(27):11263-7. Thus, antibodies may be implicated in ALS by impairing thefunction of motor neurons, interfering with the transmission of signalsbetween the brain and muscle. Free radical injury is also likely to beinvolved in ALS. A marker of oxidative stress and lipid peroxidation,4-hydroxynonenal (HNE), was elevated in the CSF of patients withsporadic ALS. Current clinical treatments for ALS (Riluzole) that reducethe amount of glutamate released do not reverse the damage already doneto motor neurons and cause side-effects such as hepatotoxicity. In ALS,CSF purification would reduce excessively high glutamate levels in CSFand reduce oxidative species, thus prolonging the lifespan of motorneurons w/o serious side effects such as liver damage, and it wouldremove autoimmune antibodies and reactive oxidative species from CSF.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of Amyotrophic lateral sclerosis (ALS) by reducing oreliminating the presence of one or more of insoluble superoxidedismutase-1 (SOD1), glutamate, neurofilament protein, and anti-GM1ganglioside antibodies in the CSF using the systems described herein.The methods comprise removing CSF from a patient, as described herein;removing at least one of insoluble superoxide dismutase-1 (SOD1),glutamate, neurofiliment protein, and anti-GM1 ganglioside antibodies orother inflammatory mediators from the CSF, and returning the endogenousCSF to the patient, wherein the removing and returning steps areperformed concurrently during at least a portion of the treatment. Insome embodiments, the insoluble superoxide dismutase-1 (SOD1),glutamate, neurofilament protein, anti-GM1 ganglioside antibodies orother inflammatory mediators are removed from the CSF using one or moreof an immunoaffinity column, a size exclusion column, an anionicexchange column, a cationic exchange column, and a Protein A or ProteinG column.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of Amyotrophic lateral sclerosis (ALS) by introducing acatheter apparatus through a spinal access site into a spinal CSF spaceof a patient; advancing the catheter apparatus through the spinal CSFspace toward the brain so that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one ofinsoluble superoxide dismutase-1 (SOD1), glutamate, neurofilamentprotein, anti-GM1 ganglioside antibodies or other inflammatory mediatorsfrom the withdrawn CSF thereby conditioning the CSF; and returning theconditioned CSF through the other of said ports.

Further embodiments for treating Amyotrophic lateral sclerosis (ALS) areas discussed above and herein.

a. Cerebral Vasospasm

Cerebral vasospasm is a time-dependent narrowing of cerebral vesselcaliber, likely due to blood in the subarachnoid space (post cerebralaneurysm rupture, subarachnoid hemorrhage (SAH), craniocerebral trauma,bacterial meningitis, after surgery in the sellar/parasellar region,etc.). See, Macdonald, R. L., R. M. Pluta, et al. (2007). Nat Clin PractNeurol 3(5): 256-63. Hemolysis is necessary for vasospasm to develop andoxyhemoglobin is believed to be one of the many vasoactive substancereleased. Elevated levels of oxyhemoglobin are maintained in the CSFover the duration of vasospasm. In contrast, most other vasoactiveagents released after clot lysis are rapidly cleared from the CSF. See,Macdonald, R. L., R. M. Pluta, et al. (2007). Nat Clin Pract Neurol3(5): 256-63. In subarachnoid patients with vasospasm, endothelin in theCSF remained at or increased above levels measured before surgery. Theincrease coincided with the appearance of vasospasm as documented bytranscranial doppler and clinical symptoms. In SAH patients who did notdevelop vasospasm, the concentration of endothelin in the CSF decreasedwith time. See, Macdonald, R. L., R. M. Pluta, et al. (2007). Nat ClinPract Neurol 3(5): 256-63. Current therapies (calcium channel blockers,hypervolemic, hypertensive therapy and hemodilution (HHH therapy)) arenot effective in preventing vasospasm. CSF filtration is more likely tobe therapeutic by early and direct removal of blood clot, red bloodcells, platelets and the downstream cascades involving oxyhemoglobin andendothelin that lead to vasospasm.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of cerebral vasospasm by reducing or eliminating thepresence of one or more of blood cells (e.g., erythrocytes), hemoglobin,oxyhemoglobin, endothelin or other inflammatory mediators in the CSFusing the systems described herein. The methods comprise removing CSFfrom a patient, as described herein; removing at least one of bloodcells, hemoglobin, oxyhemoglobin, endothelin or inflammatory mediatorsfrom the CSF, and returning the endogenous CSF to the patient, whereinthe removing and returning steps are performed concurrently during atleast a portion of the treatment. In some embodiments, the oxyhemoglobinand endothelin are removed from the CSF using one or more of animmunoaffinity column, a size exclusion column, an anionic exchangecolumn, and a cationic exchange column.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of cerebral vasospasm by introducing a catheter apparatusthrough a spinal access site into a spinal CSF space of a patient;advancing the catheter apparatus through the spinal CSF space toward thebrain so that a distal port and a proximal port on the catheterapparatus are disposed within the CSF space and spaced-apart by apreselected distance or adjusted to an appropriate distance; withdrawingCSF through one of said ports; removing at least one of blood cells,hemoglobin, oxyhemoglobin, endothelin or inflammatory mediators from thewithdrawn CSF thereby conditioning the CSF; and returning theconditioned CSF through the other of said ports.

Further embodiments for treating cerebral vasospasm are as discussedabove and herein.

i. Encephalitis

Encephalitis is inflammation of the brain due to multiple causes: HSV(herpes simplex virus), Lyme disease, syphilis, bacterial infection,etc. Infants younger than 1 year and adults older than 55 are atgreatest risk of death from encephalitis. See, Vernino, S., M.Geschwind, et al. (2007). Neurologist 13(3): 140-7. Current therapies(corticosteroids to reduce brain swelling and NSAIDs to decrease fever)do not target the cause of encephalitis. Levels of sTNF-R (reflectsbiologic activity of TNF-alpha, a major inflammatory mediator) weresignificantly higher in the CSF and serum of children with acuteencephalitis than in those of control subjects. See, Vernino, S., M.Geschwind, et al. (2007). Neurologist 13(3): 140-7. Levels of IgG wereincreased in herpes simplex encephalitis. See, Vernino, S., M.Geschwind, et al. (2007). Neurologist 13(3): 140-7. CSF processing couldrestore levels of TNF-alpha and IgG to physiologic levels, reduceinflammation and aid in removal of viruses, parasites, prions, fungi andbacteria. Further applications include treating victims of biologicwarfare (anthrax, botulinum, ricin, saxitoxin, etc.) by directlyremoving the toxin of interest from attacking the CNS.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of encephalitis by reducing or eliminating the presence ofone or more of tumor necrosis factor-alpha (TNFa) and IgG in the CSFusing the systems described herein. The methods comprise removing CSFfrom a patient, as described herein; removing at least one of TNFa andIgG or other inflammatory mediators from the CSF, and returning theendogenous CSF to the patient, wherein the removing and returning stepsare performed concurrently during at least a portion of the treatment.In some embodiments, the TNFa and IgG are removed from the CSF using oneor more of an immunoaffinity column, a size exclusion column, an anionicexchange column, a cationic exchange column and a Protein A or Protein Gcolumn.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of encephalitis by introducing a catheter apparatus througha spinal access site into a spinal CSF space of a patient; advancing thecatheter apparatus through the spinal CSF space toward the brain so thata distal port and a proximal port on the catheter apparatus are disposedwithin the CSF space and spaced-apart by a preselected distance oradjusted to an appropriate distance; withdrawing CSF through one of saidports; removing at least one of TNFa and IgG or other inflammatorymediators from the withdrawn CSF thereby conditioning the CSF; andreturning the conditioned CSF through the other of said ports.

Further embodiments for treating encephalitis are as discussed above andherein.

a. Guillain Barre Syndrome (GB S)

Guillain Barre Syndrome (GBS) is divided into the two major subtypes:acute inflammatory demyelinating polyneuropathy (AIDP) and acute motoraxonal neuropathy (AMAN). See, Parkhill, J., B. W. Wren, et al. (2000).Nature 403(6770): 665-8; and Yuki, N., K. Susuki, et al. (2004). ProcNatl Acad Sci USA 101(31): 11404-9. In Europe and North America, GBS isusually caused by AIDP with prominent lymphocytic infiltration of theperipheral nerves and macrophage invasion of myelin sheath and Schwanncells. Activated complement found in cerebrospinal fluid ofGuillain-Barre and multiple sclerosis (MS) patients may contribute todemyelination. See, Parkhill, J., B. W. Wren, et al. (2000). Nature403(6770): 665-8; and Yuki, N., K. Susuki, et al. (2004). Proc Natl AcadSci USA 101(31): 11404-9. Treatment of GBS is subdivided intosymptomatic management of severely paralyzed patients requiringintensive care and ventilatory support, and specific disease therapy tolessen the nerve damage. Immunomodulating treatments such asplasmapheresis and intravenous immunoglobulin are indicated for patientswho are unable to walk independently. Results of internationalrandomized trials have shown equivalent efficacy of both plasmapheresisand intravenous immunoglobulin, but corticosteroids are not effective.See, McKhann, G. M., J. W. Griffin, et al. (1988). Ann Neurol 23(4):347-53; and Kuwabara, S., M. Mori, et al. (2001). Muscle Nerve 24(1):54-8. Repeated filtration of CSF may remove pathogenetically relevantcells, immunoglobulins and polypeptides. Observations in 12 severeGuillain-Barre patients treated with CSF filtration indicate that it isa safe and effective procedure. CSF filtration and plasma exchangetherapies were at least equally efficacious, and a patient with severedisease who did not respond to plasma exchange recovered completely withCSF filtration. See, Wollinsky, K. H., P. J. Hulser, et al. (2001).Neurology 57(5): 774-80. CSF filtration (in vitro testing) effectivelyremoved cells and inflammatory mediators (e.g. C5a, TNF-α, IL-2, IL-6,interferon-y, IgG, endotoxins, and cells). See, Wollinsky, K. H., P. J.Hulser, et al. (2001). Neurology 57(5): 774-80. Thus, studies show thatCSF filtration is at least as effective as plasmapheresis and itreduces, limits, and prevents nerve damage by removing lymphocytes,macrophages, complement proteins and other inflammatory agents.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of Guillain Barre Syndrome (GB S) by reducing oreliminating the presence of one or more of cells and inflammatorymediators selected from the group consisting of C5a, TNF-a, IL-2, IL-6,interferon-y, IgG, and endotoxins in the CSF using the systems describedherein. The methods comprise removing CSF from a patient, as describedherein; removing at least one of cells and inflammatory mediatorsselected from the group consisting of C5a, TNF-a, IL-2, IL-6,interferon-y, IgG, and endotoxins from the CSF, and returning theendogenous CSF to the patient, wherein the removing and returning stepsare performed concurrently during at least a portion of the treatment.In some embodiments, the cells and inflammatory mediators selected fromthe group consisting of C5a, TNF-a, IL-2, IL-6, interferon-y, IgG, andendotoxins are removed from the CSF using one or more of animmunoaffinity column, a size exclusion column, an anionic exchangecolumn, a cationic exchange column and a Protein A or Protein G column.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of Guillain Bane Syndrome (GBS) by introducing a catheterapparatus through a spinal access site into a spinal CSF space of apatient; advancing the catheter apparatus through the spinal CSF spacetoward the brain so that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one ofcells and inflammatory mediators selected from the group consisting ofC5a, TNF-a, IL-2, IL-6, interferon-y, IgG, and endotoxins from thewithdrawn CSF thereby conditioning the CSF; and returning theconditioned CSF through the other of said ports.

Further embodiments for treating Guillain Bane Syndrome are as discussedabove and herein.

a. Multiple Sclerosis (MS)

Multiple sclerosis (MS) is the most common demyelinating disease inhumans and has an unknown etiology. However, it is widely accepted to bean autoimmune disease mediated by autoreactive T lymphocytes withspecificity for myelin antigens. See, Noseworthy, J. H. (1999). Nature399 (6738 Suppl): A40-7. The pathologic hallmark of the disease is theMS plaque, an area of white matter demyelination usually accompanied byinflammatory infiltrate composed of T lymphocytes, some B cells andplasma cells, activated macrophages or microglial cells. IgG andcomplement are localized primarily at the periphery of plaques. Blymphocyte clones accumulate in the CSF of MS patients and patients withother neurological disorders. Anti-myelin-oligodendrocyte glycoproteinantibodies were detected in CSF from seven of the patients with MS,compared to two with other neurological diseases and one with tensionheadache. See, Hohlfeld, R. and H. Wekerle (2004). Proc Natl Acad Sci.USA 101 Suppl 2: 14599-606. Elevated numbers of CD4+ T helper cells canbe found in the CSF during early exacerbations. Osteopontin is increasedin patients' plasma before and during relapses and was found to induceworsening autoimmune relapses and severe progression of myelinatingdiseases. See, Hohlfeld, R. and H. Wekerle (2004). Proc Natl Acad SciUSA 101 Suppl 2: 14599-606. Current therapies are limited and oftenineffective and include global immunosuppression mediated by steroids,interferon beta therapy, monoclonal antibody treatments and peptidefragments similar to myelin proteins. CSF purification would have theadvantage of depletion cell populations and alleviated the effects of MSexacerbations by: 1) removal of autoreactive CD4+ and CD8+ T cells, 2)reduction in the levels of pro-inflammatory cytokines and 3) reductionin the production of autoreactive antibodies by B cells. Depletion ofthese autoreactive cell populations also can reduce the recurrence of MSexacerbations, limit permanent damage caused by the inflammation seen inan exacerbation, and prevent lesions that mark progression of thedisease. By restricting this depletion to the CSF, the present systemsand methods addresses these issues without many of the complicationsassociated with steroid treatment or systemic immunosuppression.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of multiple sclerosis (MS) by reducing or eliminating thepresence of one or more of T cells, B cells, anti-myelin antibodies andinflammatory mediators selected from the group consisting of TNF-a,IL-2, IL-6, interferon-y in the CSF using the systems described herein.The methods comprise removing CSF from a patient, as described herein;removing at least one of T cells, B cells, anti-myelin antibodies andinflammatory mediators selected from the group consisting of TNF-a,IL-2, IL-6, interferon-y from the CSF, and returning the endogenous CSFto the patient, wherein the removing and returning steps are performedconcurrently during at least a portion of the treatment. In someembodiments, the T cells, B cells, anti-myelin antibodies andinflammatory mediators selected from the group consisting of TNF-a,IL-2, IL-6, interferon-y are removed from the CSF using one or more ofan immunoaffinity column, a size exclusion column, an anionic exchangecolumn, a cationic exchange column and a Protein A or Protein G column.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of multiple sclerosis (MS) by introducing a catheterapparatus through a spinal access site into a spinal CSF space of apatient; advancing the catheter apparatus through the spinal CSF spacetoward the brain so that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one of Tcells, B cells, anti-myelin antibodies and inflammatory mediatorsselected from the group consisting of TNF-a, IL-2, IL-6, interferon-yfrom the withdrawn CSF thereby conditioning the CSF; and returning theconditioned CSF through the other of said ports.

Further embodiments for treating multiple sclerosis (MS) are asdiscussed above and herein.

a. Stroke

Stroke occurs when a blood clot blocks an artery or a blood vesselbreaks, interrupting blood flow to an area of the brain; brain cellsthen begin to die and brain damage occurs. Free radical injury isimplicated in pathogenesis of stroke. CSF enolase was raised in patientswith transient ischemic attacks and patients with complete strokes. See,McCulloch, J. and D. Dewar (2001). Proc Natl Acad Sci USA 98(20):10989-91. A high cerebrospinal fluid enolase was always associated witha poor prognosis. Endothelin 1 (ET-1), a highly potent endogenousvasoactive peptide, exerts a sustained vasoconstrictive effect oncerebral vessels. See, Mascia, L., L. Fedorko, et al. (2001). Stroke32(5): 1185-90; and Kessler, I. M., Y. G. Pacheco, et al. (2005). SurgNeurol 64 Suppl 1: S1:2-5; discussion S1:5. Elevation of ET-1 in plasmahas been reported 1 to 3 days after ischemic stroke. Mean CSFconcentration of ET-1 in the CSF of stroke patients was 16.06.+−0.4.9pg/mL, compared with 5.51.+−0.1.47 pg/mL in the control group (P<0.001).See, Mascia, L., L. Fedorko, et al. (2001). Stroke 32(5): 1185 90; andKessler, I. M., Y. G. Pacheco, et al. (2005). Surg Neurol 64 Suppl 1:S1:2-5, discussion S1:5. Current stroke management is ineffective andincludes symptomatic treatment (surgery, hospital care, andrehabilitation) or canes a risk of brain hemorrhage (cerebralangioplasty and use of tissue plasminogen activator (tPA) to dissolveacute clot in vessel). Similarly, traumatic brain injury (TBI) or spinalcord injury (SCI) occurs when sudden trauma affects the brain or spinalcord following falls, motor vehicle accidents, assaults etc. Currenttreatment of TBI and SCI focuses on increasing independence in everydaylife and rehabilitation (i.e. individual therapy). Moderate hypothermiais thought to limit deleterious metabolic processes that can exacerbateinjury. CSF processing would allow for not only the removal ofneuroinflammatory components such as enolase, ET-1 and free radicals butprovide selective cooling to the CNS which is expected to be faster andmore effective than systemic cooling, which is limited by shivering andthe danger of severe cardiac arrhythmias.

Accordingly, the present methods provide for ameliorating or reducingthe symptoms of stroke, traumatic brain injury (TBI), spinal cord injury(SCI) by reducing or eliminating the presence of one or more ofendothelin and enolase or other inflammatory mediators in the CSF usingthe systems described herein. The methods comprise removing CSF from apatient, as described herein; removing at least one of endothelin andenolase from the CSF, and returning the endogenous CSF to the patient,wherein the removing and returning steps are performed concurrentlyduring at least a portion of the treatment. In some embodiments, theendothelin and enolase or other inflammatory mediators are removed fromthe CSF using one or more of an immunoaffinity column, a size exclusioncolumn, an anionic exchange column, a cationic exchange column and aProtein A or Protein G column. In some embodiments, the removed CSF iscooled to below physiological temperatures.

In another embodiment, the methods provide for ameliorating or reducingthe symptoms of stroke, TBI, SCI by introducing a catheter apparatusthrough a spinal access site into a spinal CSF space of a patient;advancing the catheter apparatus through the spinal CSF space craniallytoward the brain so that a distal port and a proximal port on thecatheter apparatus are disposed within the CSF space and spaced-apart bya preselected distance or adjusted to an appropriate distance;withdrawing CSF through one of said ports; removing at least one ofendothelin and enolase or other inflammatory mediators from thewithdrawn CSF and/or cooling the CSF to varying degrees therebyconditioning the CSF; and returning the conditioned CSF through theother of said ports.

Further embodiments for treating stroke are as discussed above andherein.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A system for conditioning cerebrospinal fluid(CSF), said system comprising: a catheter assembly including a firstlumen with a distal port and a second lumen with a proximal port, saidcatheter being adapted to be introduced in a CSF space and said portsbeing spaced axially apart; a pump connectable between the first andsecond lumens to induce a flow of CSF therebetween; and a conditioningcomponent connectable between the first and second lumens to conditionthe CSF flowing therebetween, wherein the catheter assembly comprises asingle tubular member having the first lumen and distal port and thesecond lumen and proximal port fixedly disposed therein, and wherein thecatheter assembly is configured to withdraw CSF through one of saidports and return CSF through the other of said ports at substantiallythe same rate.
 2. A system of claim 1, wherein the pump has a flow rateadjustable between 0.04 ml/min to 30 ml/min.
 3. A system of claim 1,wherein the pump comprises a peristaltic pump which is isolated from theCSF flow.
 4. A system of claim 1, wherein the condition component isselected from the group consisting of size exclusion, immunoaffinity,biospecific affinity, cationic exchange, anionic exchange andhydrophobicity.
 5. A system of claim 1, wherein the system has a CSFretention volume below 40 ml.
 6. The system of claim 1, wherein theconditioning component is configured to remove at least one oferythrocytes, hemoglobin, oxyhemoglobin and endothelin from the CSF. 7.The system of claim 1, wherein the conditioning component is configuredto remove at least one of alpha-synuclein fibrils and oligomers from theCSF.
 8. The system of claim 1, wherein the conditioning component isconfigured to remove at least one of insoluble superoxide dismutase-1(SOD1), glutamate, neurofilament protein, and anti-GM1 gangliosideantibodies from the CSF.
 9. The system of claim 1, wherein theconditioning component is configured to remove at least one of tumornecrosis factor-alpha (TNFa) and IgG from the CSF.
 10. The system ofclaim 1, wherein the conditioning component is configured to remove atleast one of cells and inflammatory mediators selected from the groupconsisting of C5a, TNF a, IL-2, IL-6, interferon-y, IgG, and endotoxinsfrom the CSF.
 11. The system of claim 1, wherein the conditioningcomponent is configured to remove at least one of T cells, B cells,anti-myelin antibodies and inflammatory mediators selected from thegroup consisting of TNF-a, IL-2, IL-6, interferon-y from the CSF. 12.The system of claim 1, wherein the conditioning component is configuredto remove at least one of endothelin and enolase from the CSF.
 13. Asystem for conditioning cerebrospinal fluid (CSF), the systemcomprising: a catheter having a first lumen with a first port and asecond lumen having a second port; and wherein the first lumen isconfigured to remove a cerebrospinal fluid from a first cerebrospinalfluid space in a patient; a filter coupled to the catheter, the filterbeing designed to remove one or more materials from the cerebrospinalfluid and to form a conditioned cerebrospinal fluid; wherein the secondlumen is configured to return the conditioned cerebrospinal fluid to asecond cerebrospinal fluid space; and wherein cerebrospinal fluid isremoved from the patient at a first flow rate, wherein the conditionedcerebrospinal fluid is returned to the patient at a second flow ratethat is substantially the same as the first flow rate.
 14. The system ofclaim 13, wherein the system is configured such that the flow directionsof removing the cerebrospinal fluid and returning the conditionedcerebrospinal fluid are periodically reversed.
 15. The system of claim13, wherein the filter is designed to remove meningitis-relatedsubstances.
 16. The system of claim 13, wherein the filter is designedto remove at least one of blood cells, hemoglobin, oxyhemoglobin,endothelin or inflammatory mediators from the CSF.
 17. The system ofclaim 13, wherein the filter is designed to remove at least one of Aβ ortau proteins or inflammatory mediators from the CSF.
 18. The system ofclaim 13, wherein the filter is designed to remove at least one of cellsand inflammatory mediators selected from the group consisting of C5a,TNP-α, IL-2, IL-6, interferon-γ, IgG, and endotoxins from the CSF. 19.The system of claim 13, further including one or more sensors forintermittent or continuous monitoring or sampling the cerebrospinalfluid for levels of one or more specific compounds or parameters ofinterest.
 20. The system of claim 19, wherein one or more sensors areutilized to serially sample and quantify levels of a specific compoundor molecule in the CSF, and be used as an indication of how much thesystem has conditioned the CSF.